To Fight Cancer, Know the Enemy

THE National Cancer Institute, which has overseen American efforts on researching and combating cancers since 1971, should take on an ambitious new goal for the next decade: the development of new drugs that will provide lifelong cures for many, if not all, major cancers. Beating cancer now is a realistic ambition because, at long last, we largely know its true genetic and chemical characteristics.

This was not the case when President Richard Nixon and Congress declared a “war on cancer” more than 35 years ago. As a member of the new National Cancer Advisory Board, I argued that money for “pure cancer research” would be a more prudent expenditure of federal funds than creating new clinical cancer centers. My words, however, fell on deaf ears, and the institute took on a clinical mission. My reward for openly disagreeing was being kicked off the advisory board after only two years.

While overall cancer death rates in the United States began to decrease slowly in the 1990s, cancer continues to take an appalling toll, claiming nearly 560,000 lives in 2006, some 200,000 more fatalities than in the year before the War on Cancer began. Any claim that we are still “at war” elicits painful sarcasm. Hardly anyone I know works on Sunday or even much on Saturday, as almost no one believes that his or her current work will soon lead to a big cure.

A comprehensive overview of how cancer works did not begin to emerge until about 2000, with more extensive details about specific cancers beginning to pour forth only after the 2003 completion of the Human Genome Project (a breathtaking achievement that the Italian-born virologist and Nobel laureate Renato Dulbecco foresaw in 1985 as a necessary prerequisite for a deep understanding of cancer). We shall soon know all the genetic changes that underlie the major cancers that plague us. We already know most, if not all, of the major pathways through which cancer-inducing signals move through cells. Some 20 signal-blocking drugs are now in clinical testing after first being shown to block cancer in mice. A few, such as Herceptin and Tarceva, have Food and Drug Administration approval and are in widespread use.

Unfortunately, virtually none of these new drugs leads to a lifelong cure. In most instances, they can offer only modest extensions in survival time. This is partly because there are often many types of cancer-causing genetic “drivers” within single cancer cells. While getting a DNA diagnosis for the drivers of every individual cancer would help us to prescribe more specific regimens of chemotherapy, given the inherent genetic instability of most cancer cells, the use of drugs acting against single drivers would all too soon lead to the emergence of genetic variants driven by increasingly destructive second, if not third, drivers.

Most anticancer drugs, then, will probably never reach their full potential unless they are given in combination with other drugs developed against second or even third drivers. Yet current F.D.A. regulations effectively prohibit testing in combination new drugs that, when given alone, have proved ineffective.

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Oliver Munday

While targeted combination chemotherapies would be a big step forward, I fear we still do not yet have in hand the “miracle drugs” that acting alone or in combination would stop most metastatic cancer cells in their tracks. To develop them, we may have to turn our main research focus away from decoding the genetic instructions behind cancer and toward understanding the chemical reactions within cancer cells.

The idea that cancer cells may be united in having a common set of molecules not found in most other cells of our bodies was first proposed by the great German biochemist Otto Warburg. In 1924, he observed that all cancer cells, irrespective of whether they were growing in the presence or absence of oxygen, produce large amounts of lactic acid. Yet it wasn’t until a year ago that the meaning of Warburg’s discovery was revealed: The metabolism of cancer cells, and indeed of all proliferating cells, is largely directed toward the synthesis of cellular building blocks from the breakdown products of glucose. To make this glucose breakdown run even faster in growing cells than in differentiated cells (that is, cells that have stopped growing and taken on their specialized functions in the body), the growth-promoting signal molecules turn up the levels of the “transporter” proteins that move glucose molecules into cells.

This discovery indicates that we need bold new efforts to see if drugs that specifically inhibit the key enzymes involved in this glucose breakdown have anti-cancer activity. In the late 1940s, when I was working toward my doctorate, the top dogs of biology were its biochemists, who were trying to discover how the intermediary molecules of metabolism were made and broken down.

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After my colleagues and I discovered the double helix of DNA, biology’s top dogs then became its molecular biologists, whose primary role was finding out how the information encoded by DNA sequences was used to make the nucleic acid and protein components of cells. Clever biochemists must again come to the fore to help us understand the cancer cell chemically as well as we do genetically.

While the major pharmaceutical and biotechnology corporations have the financial means to exploit their most promising drug candidates, that is not true of many of the smaller biotechnology companies that are doing highly innovative work. Their financing from venture-capital firms has drastically dwindled in this recession. The National Cancer Institute should come to their rescue, providing funds that will let their products move through animal testing to the exploratory phases of clinical testing in humans.

At the same time, the institute should provide much more money to major research-oriented cancer centers to let them take on the low probability-high payoff projects that pharmaceutical giants and, increasingly now, the big biotech companies almost reflexively turn down.

Restarting the War on Cancer has to start at the top: in 1971, Congress decided that the president, not the head of the National Institutes of Health, should appoint the director of the National Cancer Institute. Yet like all too many outposts of the White House, the institute has become a largely rudderless ship in dire need of a bold captain who will settle only for total victory. President Obama must choose strong new leadership for the institute from among our nation’s best cancer researchers; it also needs a seasoned developer of new pharmaceuticals who can radically speed up the pace at which anticancer drugs are developed and clinically tested.

I expect that my views will provoke rebuttals from prominent scientists who feel that it’s not yet the time to go all out against cancer, and that until victory is more certain we should not further tap our limited coffers for more big-cancer money. While they are right that victory will not come from money alone, neither will it come from biding our time.

James D. Watson, a winner of the 1962 Nobel Prize in Physiology or Medicine, is the chancellor emeritus of Cold Spring Harbor Laboratory.

A version of this op-ed appears in print on , on Page A29 of the National edition with the headline: To Fight Cancer, Know the Enemy. Today's Paper|Subscribe